Nutrition 26 (2010) 459–473

Review

Obesity: Genes, brain, gut, and environment

Undurti N. Das, M.D., F.A.M.S.*

UND Life Sciences, Shaker Heights, Ohio, USA; and Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, India

Manuscript received March 24, 2009; accepted September 27, 2009.

Abstract Obesity, which is assuming alarming proportions, has been attributed to genetic factors, hypothalamic

www.nutritionjrnl.com

Dr. Das received a

Biotechnology, India,

* Corresponding a

E-mail address: U

0899-9007/10/$ – see

doi:10.1016/j.nut.2009

dysfunction, and intestinal gut bacteria and an increase in the consumption of energy-dense food. Obe-

sity predisposes to the development of type 2 diabetes mellitus, hypertension, coronary heart disease,

and certain forms of cancer. Recent studies have shown that the intestinal bacteria in obese humans and

mice differ from those in lean that could trigger a low-grade systemic inflammation. Consumption of

a calorie-dense diet that initiates and perpetuates obesity could be due to failure of homeostatic mech-

anisms that regulate appetite, food consumption, and energy balance. Hypothalamic factors that reg-

ulate energy needs of the body, control appetite and satiety, and gut bacteria that participate in food

digestion play a critical role in the onset of obesity. Incretins, cholecystokinin, brain-derived neurotro-

phic factor, leptin, long-chain fatty acid coenzyme A, endocannabinoids and vagal neurotransmitter

acetylcholine play a role in the regulation of energy intake, glucose homeostasis, insulin secretion,

and pathobiology of obesity and type 2 diabetes mellitus. Thus, there is a cross-talk among the gut,

liver, pancreas, adipose tissue, and hypothalamus. Based on these evidences, it is clear that manage-

ment of obesity needs a multifactorial approach. � 2010 Elsevier Inc. All rights reserved.

Keywords: Obesity; Hypothalamus; Genes; Gut bacteria; Neuropeptide Y; Ghrelin; Leptin; Cytokines

Introduction

The incidence of obesity is increasing in developed and

developing countries and cannot be attributed to genetic fac-

tors alone because the human genes have not changed re-

cently. In general, it is believed that humans are more

suited to resist famine than overabundance of food (called

the ‘‘thrifty gene hypothesis’’) and, hence, it has been argued

that the easy and relatively inexpensive availability of en-

ergy-dense food is responsible for the current obesity epi-

demic. This coupled with lack of exercise, enhanced intake

of saturated fats, carbonated drinks, and increase in total cal-

orie intake seem to be driving the increase in the incidence of

obesity. The food that is ingested needs to be digested and as-

similated and this in turn contributes to the total amount of

calories that is available to the human body. The energy bal-

ance is very tightly controlled by hypothalamic factors.

Hence, the gut–brain axis and the cross-talk between gut hor-

Ramalingaswami Fellowship from the Department of

during the tenure of this study.

uthor. Tel.: þ216-231-5548; fax: þ928-833-0316.

ndurti@hotmail.com (U. N. Das).

front matter � 2010 Elsevier Inc. All rights reserved.

.09.020

mones and hypothalamic factors are important in the regula-

tion of food intake, energy balance, and development of

obesity. This implies that the digestive process and assimila-

tion from the small intestine play a significant role in the

amount of calories that is ultimately provided to the body.

Thus, factors that modulate the digestive process and assim-

ilation could affect human body weight. Recent studies have

revealed that bacteria present in the colon could affect energy

balance and obesity. Furthermore, some individuals may be

genetically programmed or more susceptible to develop obe-

sity partly due to environmental factors, familial tendency,

and hypothalamic dysfunction. In this review, interactions

among genes, hypothalamic factors, the gut, and environ-

ment are discussed to emphasize the complex and multifacto-

rial origin of obesity and, hence, the need for a multipronged

approach in its management.

Incidence and prevalence of obesity

It is estimated that globally there are more than 1 billion

overweight adults, with at least 300 million of them obese,

and is a major contributor to the global burden of chronic dis-

ease and disability. Often coexisting in developing countries

with undernutrition, obesity is a complex condition, with

U. N. Das / Nutrition 26 (2010) 459–473460

serious social and psychological dimensions, affecting virtu-

ally all ages and socioeconomic groups. Overweight and obe-

sity ranges are determined by using weight and height to

calculate a measurement called the ‘‘body mass index’’

(BMI). BMI is used because, for most people, it correlates

with the amount of body fat (BMI¼weight [kilograms]/

height [meters] squared] [1]:

� An adult who has a BMI from 25 to 29.9 kg/m2 is con-

sidered overweight.

� An adult who has a BMI of 30 kg/m2 or higher is con-

sidered obese.

For children and teens, BMI ranges above a normal weight

have different labels (at risk of overweight and overweight). In

addition, BMI ranges for children and teens are defined so that

they take into account normal differences in body fat between

boys and girls and differences in body fat at various ages.

Why obesity is harmful

Obesity is now recognized as a chronic disease and the sec-

ond leading cause of preventable death, exceeded only by cig-

arette smoking [2]. Obesity is a major risk factor for

hypertension, cardiovascular disease, type 2 diabetes melli-

tus, and some cancers in men and women. Other comorbid

conditions that could occur as a result of obesity include sleep

apnea, osteoarthritis, infertility, idiopathic intracranial hyper-

tension, lower extremity venous stasis disease, gastroesopha-

geal reflux, and urinary stress incontinence.

Genetics of obesity

Development of obesity depends on several genetic and

non-genetic factors. Some of them include 1) resting basal

metabolic rate (BMR), 2) thermic response to food, 3) nutri-

ent partitioning, 4) energy expenditure associated with phys-

ical activity, and 5) gene knockout and transgenic animals—

detail genes involved in obesity.

It is known that there could be individual variations in

these factors that predispose an individual to develop or resist

obesity. A significant difference has been reported with re-

spect to total energy expenditure (TEE), TEE/BMR and

TEE/BMR divided by weight, and TEE/BMR between nor-

mal athletes, Pima Indians, people in developing countries,

and others. Multiple regression analysis has shown that fat-

free mass and age are the significant variables that can ex-

plain 65% of the variation in TEE, suggesting that TEE varies

dramatically among healthy, free-living adults [3]. Examina-

tion of variation in resting energy expenditure to variation in

uncoupling protein (UCP) has suggested that resting energy

expenditure is lower in African women than in white women.

Genetic variations of UCP could be associated with child-

hood-onset obesity in African-American, white, and Asian

children [4,5], supporting the concept that an association ex-

ists between certain genetic markers and energy expenditure

and their susceptibility to develop obesity. Similarly,

FOXC2, a winged helix gene, that counteracts obesity, hy-

pertriglyceridemia, and diet-induced insulin resistance, could

be a candidate gene for susceptibility to obesity and type 2

diabetes. In Pima Indians the C-512 T variant of FOXC2

was associated with BMI (P¼ 0.03) and percentage of

body fat (P¼ 0.02) in male and female subjects and with

basal glucose turnover and fasting plasma triacylglycerols

in women, suggesting that variation in FOXC2 has a role

in body weight control and in the regulation of basal glucose

turnover and plasma triacylglycerol levels [6].

Adiponectin is an important adipokine that enhances insu-

lin sensitivity. The fact that low resting metabolism rate is as-

sociated with high serum adiponectin indicates that subjects

with low resting metabolism rate, who are theoretically at

greater risk of obesity-related disorders, are especially pro-

tected by adiponectin [7]. When a possible association be-

tween fat mass and an obesity-associated gene (FTO) and

phenotypic variation in their energy expenditure (BMR and

maximal oxygen consumption) and energy intake was stud-

ied, it was noted that the FTO genotype was significantly as-

sociated with variation in energy intake. Pima Indians

heterozygous for R165Q or NT100 in melanocortin-4 recep-

tor (MC4R) had higher BMIs and lower energy expenditure,

indicating that lower energy expenditure was a component of

the increased adiposity [8]. Thus, obesity and type 2 diabetes

mellitus are associated with variations in the expression and

genotype (including single nucleotide polymorphism) of

UCPs, FOXC2, adiponectin, FTO, MC4R, and other related

genes.

Gene expression profile in obesity

Several other genes could be upregulated or downregu-

lated in a subject with obesity [9]. Some of the upregulated

genes include vascular endothelial growth factor, fibroblast

growth factor, low-density lipoprotein receptor, adrenergic

b-receptor kinase, glycogen synthase kinase-3a, neuropep-

tide Y (NPY) receptors Y1 and Y5, and mitogen-activated

protein kinases. Genes that are downregulated in obese sub-

jects include c-fos–induced growth factor, prostaglandin E re-

ceptor, insulin receptor substrate-4, natriuretic peptide

receptor-4, and adrenergic b2-receptor, genes that are in-

volved in the regulation of cell growth (c-fos), inflammation

(prostaglandin E), and the sympathetic nervous system (ad-

renergic receptor). Thus, there seems to be a concerted upre-

gulation and downregulation of genes that may pave the way

to the development of obesity by conserving energy.

Perinatal nutritional environment and obesity

Fetal nutritional environment influences the risk of de-

veloping obesity in adult life [10–12] by influencing the

developing neuroendocrine hypothalamus, the integrative

control center for postnatal energy balance regulation.

NPY, agouti-related peptide, pro-opiomelanocortin, co-

caine- and amphetamine-regulated transcript, and insulin

U. N. Das / Nutrition 26 (2010) 459–473 461

receptor mRNAs and leptin receptor mRNA, the key cen-

tral components of adult energy balance regulation, in

early gestation [13]. Hence, perinatal and early childhood

nutrition is expected to have a programming influence on

hypothalamic neurotransmitters and thus ultimately deter-

mine the development of obesity in adulthood. This is sup-

ported by the observation that obesity and type 2 diabetes

mellitus could be disorders of hypothalamic dysfunction

and low birth weight is associated with high prevalence

of obesity, type 2 diabetes mellitus, and metabolic syn-

drome in later life [14,15]. Although some studies have

disputed these findings and suggested that postnatal nutri-

tion and growth are more important [16], this suggests that

early nutrition has a bearing on the development of obe-

sity, type 2 diabetes mellitus, and metabolic syndrome in

later life.

Obesity and type 2 diabetes mellitus as disorders of thebrain

In experimental animals, ventromedial hypothalamic

(VMH) lesions induced hyperphagia and excessive weight

gain, fasting hyperglycemia, hyperinsulinemia, hypertriglycer-

idemia, and impaired glucose tolerance. Intraventricular ad-

ministration of antibodies to NPY abolished hyperphagia in

these animals. Streptozotocin-induced diabetic animals

showed an increase in NPY concentrations in paraventricular,

VMH, and lateral hypothalamic areas. VMH-lesioned rats

showed selectively decreased concentrations of norepinephrine

and dopamine in the hypothalamus; whereas long-term infu-

sion of norepinephrine and serotonin into the VMH impaired

pancreatic islet cell function. These changes in the hypotha-

lamic neurotransmitters reverted to normal after insulin ther-

apy. This suggests that dysfunction of the VMH impairs

pancreatic b-cell function and induces metabolic abnormalities

seen in obesity and type 2 diabetes mellitus. Tumor necrosis

factor-a (TNF-a) decreases the firing rate of VMH neurons

and is neurotoxic [17–19]. In VMH-lesioned rats, the abun-

dance of obese (ob) mRNA increased after the gain of body

weight and marked expression was observed after making

a VMH lesion [20], suggesting that the ob gene is upregulated

with fat accumulation even in non-genetically obese animals.

The tone of the parasympathetic nervous system increases

after VMH lesion, whereas sympathetic tone decreases

[21,22]; as a result, lipolysis would not occur, which leads

to obesity. Acetylcholinesterase activity in the liver, pan-

creas, and stomach, known to be vagal targets, of VMH-le-

sioned obese rats was significantly increased, suggesting

that acetylcholinesterase activity is enhanced in vagus inner-

vated tissues after VMH lesion-induced obesity [22],

whereas radical vagotomies blocked the development of obe-

sity in VMH-lesioned animals. These results indicate that the

vagus serves as the neural pathway from the hypothalamus to

the visceral fat and the pancreatic b-cells to communicate

messages from the VMH to produce disturbances in metabo-

lism that leads to obesity seen in VMH-lesioned animals [23].

Vagus is the communicator from the liver to the brain

The vagus nerve also serves as the neuronal pathway in the

cross-talk between the liver and adipose tissue. In mouse, ade-

novirus-mediated expression of peroxisome proliferative-acti-

vated receptor (PPAR)-g2 in the liver induced acute hepatic

steatosis and markedly decreased the peripheral adiposity that

is accompanied by increased energy expenditure and improved

systemic insulin sensitivity. These animals not only showed in-

creased hepatic PPAR-g2 expression but also had decreased

fasting plasma glucose, insulin, leptin, and TNF-a levels, indi-

cating markedly improved insulin sensitivity, and showed de-

creased glucose output from the liver. These animals had

high tonus of the sympathetic nervous system as evidenced

by increased expression of UCP-1, peroxisomal proliferator-

activated receptor coactivator (PGC)-1a, and hormone-sensi-

tive lipase activity and serum free fatty acid levels. Resection

of the hepatic branch of the vagus nerve completely blocked

the decreases in peripheral adiposity and the increases in serum

free fatty acids, resting oxygen consumption, and UCP-1 ex-

pression, indicating that the hepatic vagus, more specifically

the afferent vagus, mediates the effects of hepatic PPAR-g2 ex-

pression [24]. Thus, selective deafferentation of the hepatic

branch of the vagus completely blocks the hepatic PPAR-g2

expression-induced decrease in peripheral adiposity, suggest-

ing that afferent vagal nerve activation originating in the liver

mediates the remote effects of hepatic PPAR-g2 expression

on peripheral tissues. Dissection of the hepatic branch of the va-

gus before thiazolidinedione administration reversed the in-

creases in resting oxygen consumption and UCP-1

expression in the adipose tissue (in white and brown adipose

tissues), indicating that the neuronal pathway originating in

the liver is also involved in the acute systemic effects of thiazo-

lidinedione in the obese subjects in whom the hepatic PPAR-g2

expression is upregulated. Thus, a neuronal pathway consisting

of the afferent vagus from the liver and efferent sympathetic

nerves to adipose tissues is involved in the regulation of energy

expenditure, systemic insulin sensitivity, glucose metabolism,

and fat distribution between the liver and the peripheral tissues.

The liver conveys information regarding energy balance to the

brain (especially the hypothalamus and in all probability to the

VMH neurons) through the afferent vagus, whereas leptin

could be the humoral signal to the brain from adipocytes.

The brain receives information from several tissues and organs

by humoral and neuronal pathways, which it would integrate to

produce appropriate responses—sympathetic nervous system

activation and/or parasympathetic modulation to maintain en-

ergy homeostasis.

Communication between liver and pancreatic b-cells ismediated by the vagus

Obesity is associated with insulin resistance that promotes

pancreatic b-cell proliferation as a compensatory response.

This in turn leads to hyperinsulinemia that is seen in early

U. N. Das / Nutrition 26 (2010) 459–473462

stages of type 2 diabetes mellitus and metabolic syndrome.

Efferent vagal signals to the pancreas modulate insulin secre-

tion and pancreatic b-cell mass [25–27]. Mutant mice selec-

tively lacking the M3 muscarinic acetylcholine receptor

subtype in pancreatic b-cells showed impaired glucose toler-

ance and greatly reduced insulin release. In contrast, trans-

genic mice selectively overexpressing M3 receptors in

pancreatic b-cells showed enhanced insulin release and in-

crease in glucose tolerance and were resistant to diet-induced

glucose intolerance and hyperglycemia, suggesting that b-

cell M3 muscarinic receptors are essential in maintaining

proper insulin release and glucose homeostasis [25]. VMH-

lesioned animals not only showed obesity and features of

type 2 diabetes mellitus but also had increase in pancreatic

weight, DNA content, and DNA synthesis due to prolifera-

tion of islet b and acinar cells that was completely inhibited

by vagotomy. This suggests that vagal hyperactivity (that

leads to an increase in the tone of parasympathetic activity)

produced by VMH lesions stimulated cell proliferation of

rat pancreatic b and acinar cells primarily through a choliner-

gic receptor mechanism [26,27]. Vagal nerve-mediated insu-

lin hypersecretion and pancreatic b-cell proliferation due to

hepatic activation of extracellular regulated kinase (ERK)

signaling are involved in this process. Afferent splanchnic

and efferent pancreatic vagal nerves play a major role in pan-

creatic b-cell expansion during diet-induced obesity develop-

ment in ob/ob and streptozotocin-induced diabetic mice [28].

Thus, hepatic ERK activation transmits signals from the liver

to the brain that activate the efferent vagus to the pancreas

that trigger pancreatic b-cell proliferation. These results indi-

cate that therapeutic manipulation of hepatic ERK activation

could be useful to trigger pancreatic b-cell mass in type 1 and

2 diabetes mellitus to regulate plasma glucose levels.

Gut-brain-liver axis—A circuit that is activated by long-chain fatty acids

The gastrointestinal tract, the first point of contact with in-

gested food, initiates a series of homeostatic mechanisms to

regulate plasma glucose levels at near normal levels during

fasting and postprandial periods. Ingested nutrients stimulate

the secretion of incretins from the gut that enhance insulin se-

cretion and initiate a gut–brain–liver axis by responding to

small amounts of triacylglycerols in the duodenum to rapidly

increase insulin secretion. Oleic acid (18:1 u-9), linoleic acid

(18:2 u-6), a-linolenic acid (18:3 u-3), arachidonic acid

(20:4 u-6), eicosapentaenoic acid (20:5 u-3), and docosa-

hexaenoic acid (22:6 u-3) that are cleaved from triacylglycer-

ols by the gastrointestinal enzymes when given at calorically

insignificant amounts markedly and rapidly increased insulin

sensitivity [29,30]. A long-chain fatty acid metabolite called

‘‘long-chain fatty acid coenzyme A’’ (LCFA-CoA), is sensed

by the intestine, probably by specific receptors that are yet to

be identified; and this lipid sensing in the gut is relayed to the

liver such that homeostatic mechanisms in place are activated

to maintain blood glucose homeostasis by enhancing

secretion of insulin from the pancreatic b-cells by the release

of incretins and by the inhibition of gluconeogenesis in the

liver. In this scheme of events the brain also plays a role

through the parasympathetic nervous system, principally by

the vagus. The LCFA-CoA sensed by the gut signals the

brain through the vagus nerve, through the hindbrain, and

then back down the vagal efferent pathway that terminates

in the liver (Fig. 1). Although the exact mechanism by which

the communication occurs between the gut and the vagus is

not clear, there could exist a role for incretins in this process

or for other gut hormones/peptides such as cholecystokinin

(CCK), leptin, or brain-derived neurotrophic factor (BDNF)

[31]. Intraduodenal perfusion of LCFAs but not medium-

chain fatty acids reduced calorie intake that could be abol-

ished by inhibition of fat hydrolysis. LCFA perfusion re-

sulted not only in a reduction in calorie intake and food

consumption but also in a concomitant increase in plasma

CCK concentrations. The use of potent and selective CCK-

A receptor antagonist completely abolished the satiation ef-

fect of LCFAs, indicating that the presence of LCFAs in

the duodenum would stimulate the release of CCK; CCK

then acts on CCK-A receptors that are present on the abdom-

inal vagus. Another possibility is that leptin may have a role

in this process because leptin gene expression and immuno-

reactivity have been reported in the gastric fundus [32] and

food ingestion causes rapid stimulation of gastric leptin se-

cretion, an effect that can be reproduced by CCK administra-

tion. In experimental animals, leptin enhanced the satiety-

inducing effect of CCK, suggesting that CCK and leptin

could function in concert with each other to induce satiety

and regulate food intake [33].

The BDNF, which regulates survival of a subpopulation

of vagal sensory neurons, is expressed in developing stomach

wall tissues innervated by vagal afferents [34]. At birth, mice

deficient in BDNF exhibited a 50% reduction of putative in-

tra-ganglionic laminar-ending mechanoreceptor precursors

and BDNF is required for patterning of individual axons

and fiber bundles in the antrum and differentiation of intra-

muscular array mechanoreceptors in the forestomach. Fur-

thermore, BDNF interacts with leptin [35], suggesting that

abnormal perinatal environments alter development of vagal

sensory innervation of the gastrointestinal tract by altering

BDNF expression and this could affect satiety and influence

food intake. Thus, LCFAs, CCK, leptin, and BDNF influence

the development of obesity.

Thus, the gut functions as an neuroendocrine organ

[29–35] that responds rapidly to energy input (food intake)

and influences the size of meals and the metabolic fate of

the ingested food by producing satiety factors such as leptin,

CCK, and BDNF, releases incretins that enhance insulin se-

cretion from pancreatic b-cells, and sends messages to the

brain by the intestine–vagus pathway, and the vagal mediator

acetylcholine and possibly BDNF that in turn could modulate

the secretion and actions of various hypothalamic neurotrans-

mitters and peptides [36–39], and, thus, the hypothalamus in-

tegrates all the messages received from the gut to regulate

Afferent Vagal fibers Efferent vagal fibers

Vagal fibers

Ach

Blood Glucose

Insulin

BDNF

CCK, Leptin

Incretins

LCFAs/PUFAs

LCFA-CoA/PUFAs-CoA

Endocannabinoids

Micr obiota

IL-6, TNF

MØ , T cells

High carbohydrate/high fat/Energy dense food

Leptin

Exercise

Brain

Hypothalamus

Food

Liver

Pancreas

Adipose

Tissue

Muscle

GU T

Fig. 1. Scheme showing the relation among diet, gut microbiota, afferent and efferent vagus nerves, blood glucose, insulin, and tissues/organs concerned with

glucose homeostasis in the pancreas, muscle, liver, adipose tissue, and brain. A diet rich in carbohydrates, saturated fats, and energy rich will lead to obesity

by causing insulin resistance and low-grade systemic inflammation. Increased consumption of PUFAs decreases insulin resistance, inhibits secretion of proinflam-

matory cytokines, and 1) leads to the formation of LCFAs-CoA, 2) enhances CCK secretion from the gut, and 3) augments the formation of endocannabinoids that

act by afferent vagal fibers on the hypothalamus to produce satiety and decrease appetite. A diet rich in PUFAs may also enhance the growth of Bacteroidetes and

inhibit that of Firmicutes that may aid in reducing obesity. PUFAs may augment the production of incretins from the gut that enhance insulin secretion from the

pancreas and enhance the production of BDNF that inhibits appetite and decreases obesity. There is a cross-talk between the liver and pancreas through vagal fibers.

Exercise reduces insulin resistance and obesity because it suppresses the production of proinflammatory cytokines, enhances the levels of BDNF in the brain, aug-

ments glucose utilization, increases vagal tone, and is anti-inflammatory in nature. In obese subjects, adipose tissue infiltrating macrophages and lymphocytes pro-

duce increased amounts of IL-6 and TNF-a, which cause low-grade systemic inflammation and insulin resistance. Leptin produced by adipose tissue and the

stomach has proinflammatory actions. Bacteroidetes are the predominant bacteria in the gut in lean animals, whereas Firmicutes are dominant in the gut of obese

animals. Firmicutes break down polysaccharides and thus provide a greater energy source for the individual that may aid the development of obesity. It is likely that

Firmicutes stimulate gut-associated lymphocytes and macrophages to produce proinflammatory cytokines. Insulin has anti-inflammatory actions, so hyperinsuli-

nemia seen in obesity and type 2 diabetes mellitus may be a compensatory phenomenon to suppress low-grade systemic inflammation seen in these conditions.

Although expression and genotype (including single nucleotide polymorphism) of uncoupling proteins, FOXC2, adiponectin, FTO (an obesity-associated

gene), melanocortin-4 receptor, and other related genes are associated with obesity, their expression and function could be modified by diet, exercise, and other

life-style related factors. Ach, acetylcholine; BDNF, brain-derived neurotrophic factor; CCK, cholecystokinin; IL-6, interleukin-6; LCFA-CoA, long-chain fatty

acid coenzyme A; LCFAs, long-chain fatty acids; MØ, macrophages; PUFA-CoA, polyunsaturated fatty acid coenzyme A; PUFAs, polyunsaturated fatty acids;

TNF, tumor necrosis factor.

U. N. Das / Nutrition 26 (2010) 459–473 463

plasma glucose levels. In this gut–brain–liver axis, the vagus

nerve seems to play a major role (Fig. 1). As discussed ear-

lier, the vagus is also important to communicate between

the liver and brain and between the liver and pancreatic b-

cells. Furthermore, as in the intestine, the LCFA-CoA mole-

cule in the hypothalamus activates neural pathways that in-

crease insulin sensitivity in the liver that also reduce food

intake [40–42]. LCFAs and their metabolite LCFA-CoA

function as a signal of nutrient intake and triggers counter-

regulatory responses that originate in the hypothalamus and

the gut to regulate plasma glucose concentrations. However,

this regulatory system quickly fades in the face of continued

ingestion of a fat-rich diet [30,41,42]. Thus, fat-rich (espe-

cially saturated fat rich) and energy-dense foods promote

obesity and diabetes, in part, by impairing nutrient-sensing

systems that are originally designed to limit food intake

and enhance insulin sensitivity. A diet rich in polyunsatu-

rated fatty acids (PUFAs) as used in the studies reported

[29–42] are important to trigger the gut–brain–liver circuit

to limit increases in plasma glucose concentrations and re-

strict the development of obesity and diabetes, whereas the

modern diets that are rich in saturated fats not only impair

U. N. Das / Nutrition 26 (2010) 459–473464

the gut–brain–liver circuit described but also do not function

efficiently to restrict food intake. This explains why PUFAs

(LCFAs) are more beneficial compared with saturated fats.

Recent studies have shown that PUFAs protect pancreatic

b-cells from chemical-induced apoptosis and thus prevent the

development of diabetes mellitus [43–46]. PUFAs (LCFAs)

also form precursors to various endocannabinoids that have

been shown to play a role in the pathobiology of obesity

and diabetes mellitus [47,48]. Furthermore, PUFAs (espe-

cially u-PUFAs) are anti-inflammatory, whereas saturated

fats are proinflammatory in nature, which accounts for low-

grade systemic inflammation and insulin resistance seen in

obesity, type 2 diabetes mellitus, and metabolic syndrome.

Insulin resistance thus may over-ride the acute insulin-sensi-

tizing effects of intestinal LCFAs (PUFAs) reported.

The gut–brain–liver circuit described may play a role in

the improvement in insulin sensitivity, amelioration of diabe-

tes, and decrease in food intake and weight loss reported after

bariatric surgery because these beneficial effects are seen

long before the weight loss is observed. Previous studies

have suggested that there are distinct changes in the hypotha-

lamic neurotransmitters and peptides that could account for

some, if not all, the beneficial actions seen after bariatric sur-

gery [49,50]. Because there are anorexigenic and orexigenic

molecules secreted by the gut, hypothalamus, and adipose tis-

sue, the final response in the form of satiety or hunger and

food consumption depends on the balance between these reg-

ulatory and counter-regulatory stimuli.

BDNF and obesity

Hypothalamic neurons play a critical role in energy homeo-

stasis. BDNF is one such factor produced by neuronal cells of

the brain that regulates functions of the gut and pancreatic b-islet

activity in response to plasma levels of glucose, protein, fatty

acids, insulin, and leptin. BDNF, present in the hippocampus,

cortex, basal forebrain, many nuclei in the brainstem, and cate-

cholamine neurons, including dopamine neurons in the substan-

tia nigra, regulates food intake and body weight in experimental

animals and humans. Systemic administration of BDNF de-

creased non-fasted blood glucose in obese, non–insulin-depen-

dent diabetic C57BLKS-Lepr(db)/lepr(db) (db/db) mice, with

a concomitant decrease in body weight. The effects of BDNF

on non-fasted blood glucose levels are not caused by decreased

food intake but reflect a significant improvement in blood glu-

cose control, an effect that persisted for weeks after cessation

of BDNF treatment. BDNF reduced the hepatomegaly present

in db/db mice, in association with lower liver glycogen and liver

enzyme activity in serum, supporting the involvement of liver

tissue in the mechanism of action for BDNF [51]. Administra-

tion of BDNF once or twice per week (70 mg $ kg�1 $ wk�1)

to db/db mice for 3 wk significantly reduced blood glucose con-

centrations and hemoglobin A1c compared with control, sug-

gesting that BDNF not only lowered blood glucose

concentrations but also restored systemic glucose balance.

These results indicated that BDNF could be a novel hypoglyce-

mic agent that has the ability to normalize glucose metabolism

even with treatment as infrequently as once per week [52]. Re-

cently, Cao et al. [53] showed the therapeutic efficacy of BDNF

by gene transfer in mouse models of obesity and type 2 diabetes

mellitus, which revealed marked weight loss and alleviation of

obesity-associated insulin resistance.

BDNF and type 2 diabetes mellitus in humans

Intracerebroventricular administration of BDNF lowered

blood glucose, increased pancreatic insulin content, en-

hanced thermogenesis and norepinephrine turnover, and in-

creased UCP-1 mRNA expression in the interscapular

brown adipose tissue of db/db mice [54]. These evidences in-

dicate that BDNF activates the sympathetic nervous system

by the central nervous system and regulates energy expendi-

ture in obese diabetic animals.

Suwa et al. [55] reported that plasma levels of BDNF were

decreased in humans with type 2 diabetes independently of

obesity and inversely associated with fasting plasma glucose,

but not with insulin. BDNF output from the human brain was

inhibited when blood glucose levels were elevated, whereas

when plasma insulin was increased while maintaining normal

blood glucose, the cerebral output of BDNF was not inhibited,

indicating that high levels of glucose, but not insulin, inhibit the

output of BDNF from the human brain. These results empha-

size that low levels of BDNF accompany impaired glucose me-

tabolism, and decreased BDNF may be a factor involved in

type 2 diabetes [55]. BDNF is an anorexigenic factor that is

highly expressed in VMH nuclei. Its concentrations in the brain

are regulated by feeding status. Stress hormone corticosterone

decreased the expression of BDNF in rats and led to an eventual

atrophy of the hippocampus, suggesting that BDNF has a criti-

cal role in obesity and type 2 diabetes mellitus [56,57].

Insulin, melanocortin, and BDNF

Insulin acts as an adiposity signal to the brain [58] by its

action on the arcuate nucleus of the hypothalamus that in

turn controls energy homeostasis [58,59]. Insulin stimulates

the synthesis of pro-opiomelanocortin that acts on melano-

cortin receptors MC3R and MC4R in hypothalamic nuclei

[60]. The MC4R has a critical role in regulating energy bal-

ance and mutations in the MC4R gene result in obesity in

mice and humans. BDNF is expressed at high levels in the

VMH, where its expression is regulated by nutritional state

and by MC4R signaling. Similar to MC4R mutants, mouse

mutants that express the BDNF receptor TrkB at a quarter

of the normal amount showed hyperphagia and excessive

weight gain on higher-fat diets. BDNF infusion into the brain

suppressed the hyperphagia and excessive weight gain ob-

served on higher-fat diets in mice with deficient MC4R sig-

naling [57]. These results suggest that MC4R signaling

controls BDNF expression in the VMH and support the hy-

pothesis that BDNF is an important effector through which

MC4R signaling controls energy balance.

U. N. Das / Nutrition 26 (2010) 459–473 465

Ghrelin, leptin, and BDNF

Ghrelin, a gut hormone that increases food intake, is pro-

duced in the epithelial cells lining the fundus of the stomach,

with smaller amounts produced in the placenta, kidney, pitu-

itary, and hypothalamus. Ghrelin stimulates growth hormone

secretion and regulates energy balance by acting on the arcu-

ate nucleus of the hypothalamus [61]. In rodents and hu-

mans, ghrelin functions to increase hunger through its

action on hypothalamic feeding centers. Blood concentra-

tions of ghrelin are lowest shortly after consumption of

a meal, and then rise during the fast just before the next

meal. Intracerebroventricular injections of ghrelin increased

glucose utilization rate of white and brown adipose tissues

and strongly stimulated feeding in rats and increased body

weight gain [62]. Factors that regulate ghrelin secretion

and action include plasma glucose, insulin, acetylcholine

levels in the brain, leptin, BDNF, and various other neuro-

transmitters and peptides [62–64].

Leptin, an adiposity hormone produced by the white ad-

ipose tissue, stomach, mammary gland, placenta, and skele-

tal muscle, shows similar traits to that of insulin in action. It

reflects total fat mass, especially subcutaneous fat of the

body. Leptin prevents obesity by inhibiting appetite because

rodents and patients lacking leptin or functional leptin re-

ceptors developed hyperphagia and obesity [65]. Leptin

acts on the hypothalamus and other areas in the brain

through the neuronal circuits, stimulates the enzymes in-

volved in lipid metabolism, reduces feeding, and increases

energy expenditure by directly suppressing NPY and in-

creasing pro-opiomelanocortin. Arcuate neurons expressing

these peptides project to the paraventricular nucleus and lat-

eral hypothalamic area, resulting in increases in corticotro-

phin-releasing hormone and thyrotropin-releasing hormone

and reductions in Melanin-concentrating hormone (MCH)

and orexins [66]. Leptin acts centrally to increase insulin ac-

tion in the liver. Congenital leptin deficiency decreases brain

weight, impairs myelination, and reduces several neuronal

and glial proteins [67]; deficits are partially reversible in

adult Lepob/ob mice by leptin [67]. Furthermore, there is

a close interaction between leptin and BDNF [35]. Thus,

BDNF plays a significant role in the regulation of appetite,

obesity, and development of type 2 diabetes mellitus by its

actions on the hypothalamic neurons and modulating the se-

cretion and actions of leptin, ghrelin, insulin, NPY, melano-

cortin, serotonin, dopamine, and other neuropeptides,

neurotransmitters, and gut hormones. Hence, selective deliv-

ery BDNF to hypothalamus is useful in the management of

obesity, type 2 diabetes mellitus, and metabolic syndrome as

shown by Cao et al. [53].

Obesity and type 2 diabetes mellitus are low-grade systemicinflammatory conditions

Obesity is a low-grade systemic inflammatory condition

[11,12,17,68] and is frequently associated with insulin

resistance, hyperinsulinemia, hypertension, hyperlipidemia,

and coronary heart disease (CHD), which form core compo-

nents of metabolic syndrome. Perilipins, whose concentra-

tions are increased in obesity [69], also have

proinflammatory actions. An increase in intramyocellular

lipid, common in obesity, is associated with enhanced levels

of inflammatory markers [70], and its decrease with diet con-

trol and exercise reduces the levels of inflammatory indices

[69].

Plasma levels of C-reactive protein (CRP), TNF-a, and in-

terleukin-6 (IL-6), markers of inflammation, are elevated in sub-

jects with obesity, insulin resistance, essential hypertension,

type 2 diabetes, and CHD before and after the onset of these dis-

eases [71–76]. Overweight children and adults showed a direct

correlation between the degree of adiposity and plasma CRP

levels. Elevated CRP concentrations were associated with an in-

creased risk of CHD, ischemic stroke, peripheral arterial dis-

ease, and ischemic heart disease mortality in healthy men and

women. A strong relation between elevated CRP levels and car-

diovascular risk factors fibrinogen, and high-density lipoprotein

cholesterol was also reported.

Increased expression of IL-6 in adipose tissue and its re-

lease into the circulation is responsible for elevated CRP con-

centrations because IL-6 enhances the production of CRP in

the liver. Overweight and obese subjects have significantly

higher serum levels of TNF-a levels compared with lean sub-

jects. Weight reduction and/or exercise decrease serum con-

centrations of TNF-a. The negative correlation observed

between plasma TNF-a and high-density lipoprotein choles-

terol, glycosylated hemoglobin, and serum insulin concentra-

tions explain why CHD is more frequent in obese compared

with healthy or lean subjects [71].

Subjects with elevated CRP levels were two times more

likely to develop diabetes at 3 to 4 y of follow-up [77]. CRP

levels higher than 3.0 mg/L were significantly associated

with increased incidence of myocardial infarction, stroke, cor-

onary revascularization, or cardiovascular death [78]. Dietary

glycemic load was significantly and positively associated

with plasma CRP in healthy middle-aged women [79], sug-

gesting that hyperglycemia induces inflammation. CRP

bound to ligands exposed in damaged tissue and activated

complement [80] that led to increases in the size of myocardial

and cerebral infarcts in rats subjected to coronary and cerebral

artery ligation, respectively [81,82]. Human CRP activated

complement and 1,6-bis(phosphocholine)-hexane, a specific

small molecule inhibitor of CRP, abrogated the increase in in-

farct size and cardiac dysfunction produced by injection of hu-

man CRP in rats [83]. This suggests that inhibition of CRP

may prevent cardiac and possibly neuronal damage.

An acute increase in plasma glucose levels in subjects

with and without impaired glucose tolerance increased

plasma IL-6, TNF-a, and IL-18 levels that were much higher

and lasted longer in subjects with impaired glucose tolerance

compared with control [84]. TNF-a secretion was suppressed

in younger subjects in response to glucose challenge, but not

in the older subjects [85], and hyperglycemia induced the

U. N. Das / Nutrition 26 (2010) 459–473466

production of acute-phase reactants from the adipose tissue

[86]. These data suggest that type 2 diabetes in the elderly

could be due to alterations in the homeostatic mechanisms

that control TNF-a, IL-6, and CRP levels and that low-grade

systemic inflammation plays a significant role in the develop-

ment of type 2 diabetes.

BDNF and inflammation

Because low-grade systemic inflammation occurs in obe-

sity and type 2 diabetes mellitus and BDNF is involved in

their pathobiology, it is anticipated that BDNF may modulate

inflammation. Peripheral inflammation induced an increased

expression of BDNF mRNA which was mediated by nerve

growth factor (NGF) in the dorsal root ganglion. Significant

increases in the percentage of BDNF-immunoreactive neuron

profiles in the L5 dorsal root ganglion and marked elevation

in the expression of BDNF-immunoreactive terminals in the

spinal dorsal horn were observed after peripheral tissue in-

flammation produced by an intraplantar injection of Freund’s

adjuvant into the rat paws, suggesting that peripheral tissue

inflammation induces an increased BDNF synthesis in the

dorsa root ganglion and an elevated anterograde transport

of BDNF to the spinal dorsal horn [87]. Similar to NGF,

even BDNF might have a role n inflammation and hyperalge-

sia as supported by the observation that after 2 h of induction

of bladder inflammation there were significant increases in

levels of NGF, BDNF, and neurotrophin-3 mRNAs. The

rapid elevation of NGF, BDNF, and neurotrophin-3 corre-

sponding to the sensory and reflex changes during bladder in-

flammation [88] suggests that these neurotrophic factors have

a role in the inflammatory response.

In the bronchoalveolar lavage fluid from patients with

asthma after segmental allergen provocation, a significant in-

crease in the neurotrophins NGF, BDNF, and neurotrophin-3

was noted, suggesting that neurotrophins could play a role in

inflammation and airway hyper-responsiveness in allergic

bronchial asthma [89]. BDNF has potent effects on neuronal

survival and plasticity during development and after injury.

Activated human T cells, B cells, monocytes, and, in partic-

ular, T-helper type 1- and 2-type CD4þ T-cell lines that are

specific for myelin autoantigens such as myelin basic protein

or myelin oligodendrocyte glycoprotein secrete bioactive

BDNF with antigen stimulation. BDNF immunoreactivity

is demonstrable in inflammatory infiltrates in the brains of pa-

tients with acute disseminated encephalitis and multiple scle-

rosis, indicating that in the nervous system, inflammatory

infiltrates may have a neuroprotective effect [90]. Thus,

BDNF and other neurotrophins have two functions: to protect

the brain neurons from inflammatory events [91,92] and in

the respiratory tract, peripheral nerves, and urinary bladder

may function as proinflammatory molecules [93–95]. It is

noteworthy that BDNF is present not only in brain neurons

but also in several other tissues such as salivary glands, stom-

ach, duodenum, ileum, colon, lung, heart, liver, pancreas,

kidney, oviduct, uterus, bladder, and monocytes and

eosinophils [96–98]. BDNF is involved in other inflamma-

tory diseases such as rheumatologic conditions [99–101],

myocardial injury in the aging heart [102], inflammatory

bowel disease [103,104], atopic dermatitis [105], and other

conditions. Because BDNF is present in many tissues and

in some tissues/organs, BDNF appears to induce inflamma-

tion, caution needs to be exercised in the use of BDNF in

the clinic.

Gut bacteria and obesity

The food that is ingested needs to be digested and assim-

ilated and this in turn contributes to the total amount of calo-

ries that is available to the human body, implying that factors

that modulate the digestive process and assimilation could af-

fect human body weight. Hence, it is no surprise that human

gut bacteria play a role in obesity. Trillions of bacteria collec-

tively termed microbiota reside in the human gastrointestinal

tract and have been shown to play a role in the pathobiology

of obesity.

Gut flora, diet, obesity, and inflammation

The microbiota of the human gut is dominated by the

Firmicutes and Bacteroidetes. These phyla of bacteria are be-

nign, although a few are pathogenic. The Firmicutes is the

largest bacterial phylum containing more than 250 genera.

Some of the genera in the Firmicutes phyla include Lactoba-cillus, Mycoplasma, Bacillus, and Clostridium. There are

variations in the phylum. For instance, the Clostridium spe-

cies are obligate anaerobes, whereas members of the Bacillusform spores and many of them are obligate aerobes. Strepto-coccus pyogenes that causes infections in humans is also

a member of the Firmicutes phylum. In contrast to the Firmi-cutes, the Bacteroidetes contain about 20 genera and Bacter-oidetes thetaiotaomicron is the most abundant organism in

this group. Bacteroidetes are obligate anaerobes and are be-

nign inhabitants of the human gut. These Bacteroidetes are

opportunistic pathogens and cause disease especially after in-

testinal surgery or perforation of the gut [106,107]. It is likely

that there could be many more unidentified gut bacteria that

may have a role in human obesity. In obese humans, the pre-

dominant gut bacteria are the Firmicutes. When obese indi-

viduals lost weight, the proportion of Firmicutes became

more like that of lean individuals [106,107]. The Firmicutesare rich in enzymes that break down hard-to-digest dietary

polysaccharides, leading to their digestion and absorption,

so the host could become obese. When microbiota from the

obese animals were transferred to the lean, mice given the mi-

crobiota from obese mice extracted more calories from their

food and gained weight, suggesting that gut microflora play

a role in the development of obesity [108,109]. In an analysis

of 5088 bacterial 16S rRNA gene sequences from the cecal

microbiota of genetically obese ob/ob mice, lean ob/þ and

wild-type siblings, and their ob/þ mothers, all fed the same

polysaccharide-rich diet, it was observed that the majority

U. N. Das / Nutrition 26 (2010) 459–473 467

of mouse gut species were unique; the mouse and human mi-

crobiota were similar at the superkingdom level, with Firmi-cutes and Bacteroidetes dominating. Microbial-community

composition was found to be inherited from mothers and

compared with lean mice, and regardless of kinship, ob/obanimals showed a 50% reduction in the abundance of Bacter-oidetes and a proportional increase in Firmicutes [110].

These results reconfirmed the previous observations [106–

109] that leanness and obesity are associated with specific

gut microbiota. Germ-free (GF) mice are protected against

obesity induced by a Western-style, high-fat, and sugar-rich

diet. When adult GF mice were conventionalized (i.e., the ce-

cal content of 8-wk-old conventionally raised mouse that

contained their microbiota were given to a 7- to 10-wk-old

GF mouse) showed 60% increase in body fat, insulin resis-

tance, and hyperleptinemia within 14 d of conventionaliza-

tion, suggesting that gut microbiota influence the

development of obesity [111]. The lean phenotype seen in

GF mice has been attributed to increased skeletal muscle

and liver levels of phosphorylated adenosine monophos-

phate–activated protein kinase and its downstream targets in-

volved in fatty acid oxidation and elevated levels of PGC-1a

that increase fatty acid metabolism. In contrast, GF knockout

mice lack fasting-induced adipose factor (Fiaf), a circulating

lipoprotein lipase inhibitor whose expression is normally se-

lectively suppressed in the gut epithelium by the gut micro-

biota and, hence, is not protected from diet-induced

obesity. The GF Fiat�/� animals exhibited similar levels of

phosphorylated adenosine monophosphate–activated protein

kinase as their wild-type littermates in the liver and gastroc-

nemius muscle, but showed reduced expression of PGC-1a

and enzymes involved in fatty acid oxidation that accounted

for their propensity to develop diet-induced obesity [112].

Bacterial populations from the gut of genetically lean and

obese pigs fed a low- or high-fiber diet (0% or 50% alfalfa

meal, respectively) revealed that the total bacterial culture

counts in rectal samples declined 56% and 63% in lean and

obese animals, respectively, after feeding the high-fiber

diet. The number of cellulolytic bacteria in rectal samples

of lean-genotype pigs fed the high-fiber diet increased; how-

ever, these increases were not seen in the obese pigs [113].

These data confirm that a high-fiber diet (that helps in reduc-

ing obesity) is beneficial, in part, because it is able to enhance

cellulolytic bacterial content in the gut, especially in the lean

animals. Although the specific species of cellulolytic bacteria

in this study was not identified, it is possible that the high-fi-

ber diet fed animals showed an increase in Bacteroidetes and

a proportional decrease in Firmicutes. Gut bacteria could in-

fluence the development of obesity, in part, by altering the

expression of Gpr41, a G protein-coupled receptor expressed

by a subset of enteroendocrine cells in the gut epithelium.

Gpr41 plays a key role in the microbial–host communication

circuit. Short-chain fatty acids and their products formed as

a result of microbial fermentation of dietary polysaccharides

interacting with Gpr41, leading to an increase in the produc-

tion of enteroendocrine cell-derived hormones such as pep-

tide tyrosine tyrosine that increase absorption of short-

chain fatty acids, which are used as substrates for lipogenesis

in the liver that ultimately leads to obesity [114]. Thus, a close

interaction exists among dietary fiber, diet, gut microbiota,

gut hormones, and obesity. How can these data be correlated

to the low-grade systemic inflammation seen in obesity? In

a study of 1015 subjects, a positive correlation was observed

between plasma lipopolysaccharide (LPS) concentration and

fat and energy intakes. In a multivariate analysis, endotoxe-

mia was independently associated with energy intake. Mice

fed a high-energy diet showed an increase in plasma LPS

and the increase in LPS was more evident in mice fed

a high-fat diet compared with those that received a high-car-

bohydrate diet. Fat is a more efficient transporter of bacterial

LPS from the gut lumen into the bloodstream [115] that in

turn stimulates macrophages and lymphocytes to secrete in-

flammatory cytokines TNF-a and IL-6. Thus, a high-fat

diet enhances the proliferation of Firmicutes, augments the

production of peptide tyrosine tyrosine, increases the absorp-

tion of LPS, and this in turn induces low-grade systemic in-

flammation. It is likely that a high-fat diet–induced

proliferation of Firmicutes may also stimulate gut-associated

lymphocytes that could release larger amounts of TNF-a and

IL-6, but this remains to be confirmed.

Gastric bypass surgery for obesity induces changes in gutbacteria and hypothalamic factors

One of the options offered for extreme obesity is gastric

bypass surgery that produces significant weight loss and ame-

lioration from type 2 diabetes mellitus and insulin resistance.

After gastric bypass, a large shift in the bacterial population

of the gut was noted. Firmicutes were dominant in normal-

weight and obese individuals but significantly decreased in

individuals after gastric bypass [116]. Open Roux-en-Y gas-

tric bypass surgery produced greater inhibition of innate im-

munity [117]. This inhibition was not accounted for by

phenotypic changes in lymphocytes as assessed by flow cy-

tometry. Microarray analysis of the preoperative and day 2

specimens identified a 20-gene signature that correlated

with the surgical approach. These data suggest that obesity

and its treatment produce changes in the gut microbiota

and immune response and immunocytes, suggesting a close

interaction among genes, gut, immune response, and obesity.

A significant decrease in body weight in rats after Roux-

en-Y gastric bypass surgery was observed that was

accompanied by a decrease in NPY in the arcuate nucleus

of the hypothalamus and paraventricular nucleus and an in-

crease in a-melanocyte–stimulating hormone in arcuate and

paraventricular nuclei and a concomitant increase in seroto-

nin receptor (5-HT-1B receptor) in the paraventricular nu-

cleus [118–120]. These results emphasize the close

interaction among genes, brain, gut and gut bacteria and hor-

mones, and immunocytes in the pathobiology of obesity

[121,122] that is a complex and multifactorial systemic dis-

ease that seems to have its origins in the perinatal period.

U. N. Das / Nutrition 26 (2010) 459–473468

Insulin signaling in the brain in obesity

Insulin signaling has a role in the regulation of food in-

take, neuronal growth, and differentiation by regulating neu-

rotransmitter release and synaptic plasticity in the central

nervous system. Neuron-specific disruption of the insulin-re-

ceptor gene (NIRKO) in mice induces obesity, insulin resis-

tance, hyperinsulinemia, and type 2 diabetes without

interfering with brain development [121–123]. This indicates

that a decrease in the number of insulin receptors, defects in

the function of insulin receptors, and insulin lack or resis-

tance in the brain leads to the development of obesity and

type 2 diabetes mellitus even when pancreatic b-cells are nor-

mal. Intraventricular injection of insulin inhibits food intake

and the site of insulin action is on the hypothalamic NPY net-

work. Insulin enhances the formation of PUFAs (or LCFAs),

whereas PUFAs augment the action of insulin and the num-

ber of insulin receptors. Further, insulin and PUFAs augment

the formation of endothelial nitric oxide, a potent neurotrans-

mitter that seems to transmit the messages (probably by red

blood cells that are known to carry nitric oxide) from VMH

neurons to pancreatic b-cells and vice versa to control insulin

secretion. This suggests that maintaining adequate amounts

of insulin and insulin receptors in the brain is necessary to

control appetite and obesity (BMI), maintain normoglyce-

mia, and control inflammation [121,122].

These results imply that factors that regulate insulin action

in the brain are important in the control of obesity and type 2 di-

abetes mellitus; this is especially so because the hypothalamus

is rich in insulin receptors and drugs that specifically bind to

insulin receptors in the brain to decrease appetite, obesity,

and plasma glucose levels. In another study, it was reported

that infusion of oleic acid in the third ventricle resulted in

a marked decline in the plasma insulin concentration and

a modest decrease in the plasma glucose concentration [45].

These changes were detected within 1 h of oleic acid infusion.

Oleic acid did not alter glucose uptake but suppressed the rate

of glucose production and enhanced hepatic insulin action by

the activation of potassium adenosine triphosphate channels

in the hypothalamus. Oleic acid also decreased the hypotha-

lamic expression of NPY, suggesting that unsaturated fatty

acids control food intake by their action on hypothalamic cen-

ters. PUFAs have the ability to enhance BDNF production

[124,125] and they (PUFAs) modulate the production and ac-

tions of neurotransmitters such as serotonin, dopamine, NPY,

and melanocyte-stimulating hormone that regulate appetite,

satiety, and food intake [126,127]. These evidences tempt

one to speculate that dietary PUFAs (or LCFAs) could form

complexes with BDNF derived from gut and reach the brain

to regulate food intake, glucose and insulin production, and

energy homeostasis. Because PUFAs are present in several

tissues including the liver, muscle, and pancreas, it is likely

that local concentrations of PUFAs may regulate the produc-

tion and action of BDNF. Thus, PUFAs and BDNF could par-

ticipate in the gut–brain–liver axis (Fig. 1).

Conclusions

It is evident from the preceding discussion that muscle, ad-

ipose cells, the pancreas, the liver, and hypothalamic neurons

communicate with each other to maintain energy homeostasis

by neural and humoral pathways. For instance, gut peptides

ghrelin, CCK, and incretins interact with hypothalamic neu-

rons and signal hunger and satiety sensations by vagal afferent

neurons. BDNF present in the duodenum, ileum, colon, liver,

and pancreas [96] interacts with PUFAs to influence insulin

secretion, production of proinflammatory cytokines, and glu-

cose homeostasis through the vagus. Vagal afferent neurons

express leptin and CCK-1 to influence food intake by reduc-

ing meal size and enhancing satiation [128]. Injection of ad-

eno-associated viral vectors encoding leptin increased

hypothalamic leptin expression in ob/ob mice; suppressed

body weight and adiposity; decreased dark-phase food intake;

suppressed plasma levels of adiponectin, TNF-a, free fatty

acids and insulin, concomitant with normoglycemia; and ele-

vated ghrelin levels, whereas ghrelin readily stimulated feed-

ing in controls and was ineffective in wild-type mice treated

with adeno-associated viral vectors encoding leptin. These re-

sults indicate that ghrelin and leptin interact with each other to

regulate energy homeostasis and metabolism [129]. In addi-

tion, ghrelin significantly increased NPY and agouti-related

protein mRNA expression in the hypothalamus [130], sug-

gesting that ghrelin and NPY interact with each other. Ghrelin

facilitates cholinergic and tachykininergic excitatory path-

ways through the vagus nerve [131]. Thus, sympathetic and

parasympathetic (especially vagus) nerves carry messages

from the peripheral tissues and pancreatic b-cells to the hypo-

thalamus and vice versa to regulate overall energy balance.

Afferent vagus nerves from the liver and efferent sympa-

thetic nerves to adipose tissues regulate energy expenditure,

systemic insulin sensitivity, glucose metabolism, and fat

distribution between the liver and the periphery [24]. Proin-

flammatory cytokine production is regulated by the efferent

vagal ‘‘cholinergic anti-inflammatory pathway’’ mediated

by acetylcholine [132–134], which is a neurotransmitter

and regulator of release and actions of serotonin, dopamine,

and other neuropeptides [135]; whereas PUFAs (LCFAs)

influence acetylcholine release [136,137] and insulin sensi-

tivity [138–143], suggesting that an interaction(s) exists

among these molecules in the regulation of energy homeo-

stasis. Brain insulin resistance exists in peripheral insulin

resistance, especially in regions subserving appetite and re-

ward [144]; and exercise enhances the sensitivity of

hypothalamus to the actions of leptin and insulin and the

appetite-suppressive actions of exercise are mediated by

the hypothalamus [145].

Unsaturated fatty acids, fatty acid synthase inhibitors,

leptin, and insulin decrease plasma insulin and glucose con-

centrations and suppress hypothalamic NPY and the rate of

glucose production by activating potassium adenosine

phosphate channels in the hypothalamus [146–151]. Fatty

U. N. Das / Nutrition 26 (2010) 459–473 469

acid synthase inhibitors induced an increase in malonyl-

CoA–mediated nutrient-stimulated insulin secretion in the

pancreatic b-cell. Concentrations of malonyl-CoA also

serve as a fuel status signal in the hypothalamic neurons.

Hypothalamic neuronal PUFA content modulates the ex-

pression of NPY [152] and thus regulates food intake.

Hence, regulation of adenosine triphosphate–sensitive Kþ

channels could be a common pathway by which nutrients

modulate neuronal sensing of fuels. Exercise prevents and

helps in the management of obesity and type 2 diabetes

mellitus by 1) enhancing energy expenditure, 2) increasing

brain BDNF levels [153], 3) decreasing plasma and pancre-

atic b-cell content of IL-6 and TNF-a [154–156], 4) in-

creasing parasympathetic tone [157], 5) increasing the

utilization of PUFAs, and 6) serving as an anti-inflamma-

tory vehicle. Thus, the multipronged approach of obesity

management should include diet control, consumption of

increased amounts of PUFAs (especially u-3) and dietary

fiber, and moderate exercise (Fig. 1).

References

[1] Davis MM, McGonagle K, Schoeni RF, Stafford F. Grandparental and

parental obesity influences on childhood overweight: implications for

primary care practice. J Am Board Fam Med 2008;21:549–54.

[2] Eckel RH. Obesity and heart disease. Circulation 1997;96:3248–50.

[3] Schultz LO, Schoeller DA. A compilation of total daily energy expen-

ditures and body weights in healthy adults. Am J Clin Nutr 1994;

60:676–81.

[4] Kimm SY, Glynn NW, Aston CE, Damcott CM, Poehlman ET,

Daniels SR, Ferrell RE. Racial differences in the relation between un-

coupling protein genes and resting energy expenditure. Am J Clin

Nutr 2002;75:714–9.

[5] Yanovski JA, Diament AL, Sovik KN, Nguyen TT, Li H, Sebring NG,

Warden CH. Associations between uncoupling protein 2, body com-

position, and resting energy expenditure in lean and obese African

American, white, and Asian children. Am J Clin Nutr 2000;

71:1405–20.

[6] Kovacs P, Lehn-Stefan A, Stumvoll M, Bogardus C, Baier LJ. Genetic

variation in the human winged helix/forkhead transcription factor

gene FOXC2 in Pima Indians. Diabetes 2003;52:1292–5.

[7] Ruige JB, Ballaux DP, Funahashi T, Mertens IL, Matsuzawa Y, Van

Gaal LF. Resting metabolic rate is an important predictor of serum adi-

ponectin concentrations: potential implications for obesity-related dis-

orders. Am J Clin Nutr 2005;82:21–5.

[8] Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C,

Baier LJ. Lower metabolic rate in individuals heterozygous for either

a frameshift or a functional missense MC4R variant. Diabetes 2008;

57:3267–72.

[9] Gomez-Ambrosi J, Catalan V, Diez-Caballero A, Martinez-Cruz LA,

Gil MJ, Garcia-Foncillas J, et al. Gene expression profile of omental

adipose tissue in human obesity. FASEB J 2004;18:215–7.

[10] Das UN. Perinatal nutriiton and obesity. Br J Nutr 2008;99:1391–2.

[11] Das UN. Perinated supplementation of long-chain polyunsaturated

fatty acids, immune response, and adult diseases. Med Sci Monit

2004;10:HY 19–25.

[12] Das UN. Is metabolic syndrome X a disorder of the brain with the ini-

tiation of low-grade systemic inflammatory events during the perinatal

period? J Nutr Biochem 2007;18:701–13.

[13] Adam CL, Findlay PA, Chanet A, Aitken RP, Milne JS, Wallace JM.

Expression of energy balance regulatory genes in the developing

ovine fetal hypothalamus at midgestation and the influence of hyper-

glycemia. Am J Physiol Regul Integr Comp Physiol 2008;

294:R1895–900.

[14] Das UN. A perinatal strategy for preventing adult disease: the role of

long-chain polyunsaturated fatty acids. Boston: Kluwer Academic

Publishers; 2002.

[15] Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type

2 (non-insulin dependent) diabetes mellitus, hypertension, and hyper-

lipidemia (syndrome X): relation to reduced fetal growth. Diabetologia

1993;36:62–7.

[16] Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease—the

hypothesis revisited. BMJ 1999;319:245–9.

[17] Das UN. Is obesity an inflammatory condition? Nutrition 2001;

17:953–66.

[18] Gold RM, Quackenbush PM, Kapatos G. Obesity following combina-

tion of rostrolateral to VMH cut and contralateral mammillary area le-

sion. J Comp Physiol Psychol 1972;79:210–8.

[19] King BM, Smith RL, Frohman LA. Hyperinsulinemia in rats with ven-

tromedial hypothalamic lesions: role of hyperphagia. Behav Neurosci

1984;98:152–5.

[20] Funahashi T, Shimomura I, Hiraoka H, Arai T, Takahashi M,

Nakamura T, et al. Enhanced expression of rat obese (ob) gene in ad-

ipose tissues of ventromedial hypothalamus (VMH)-lesioned rats. Bi-

ochem Biophys Res Commun 1995;211:469–75.

[21] Paes AM, Carniatto SR, Francisco FA, Brito NA, Mathias PC. Acetyl-

cholinesterase activity changes on visceral organs of VMH lesion-

induced obese rats. Int J Neurosci 2006;116:1295–302.

[22] Sakaguchi T, Bray GA, Eddlestone G. Sympathetic activity following

paraventricular or ventromedial hypothalamic lesions in rats. Brain

Res Bull 1988;20:461–5.

[23] Cox JE, Powley TL. Prior vagotomy blocks VMH obesity in pair-fed

rats. Am J Physiol Endocrinol Metab 1981;240:E573–83.

[24] Uno K, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Imai J, et al.

Neuronal pathway from the liver modulates energy expenditure and

systemic insulin sensitivity. Science 2006;312:1656–9.

[25] Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH, et al.

Role of the M3 muscarinic acetylcholine receptor in beta-cell function

and glucose homeostasis. Diabetes Obes Metab 2007;9(Suppl

2):158–69.

[26] Edvell A, Lindstrom P. Vagotomy in young obese hyperglycemic

mice: effects on syndrome development and islet proliferation. Am

J Physiol Endocrinol Metab 1998;274(6 Pt 1):E1034–9.

[27] Kiba T, Tanaka K, Hoshino M, Misugi K, Inoue S. Ventromedial hy-

pothalamic lesion-induced vagal hyperactivity stimulates rat pancre-

atic cell proliferation. Gastroenterology 1996;110:885–93.

[28] Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H, et al.

Regulation of pancreatic b cell mass by neuronal signals from the

liver. Science 2008;322:1250–4.

[29] Thaler JP, Cummings DE. Food alert. Nature 2008;452:941–2.

[30] Wang PYT, Caspi L, Lam CKL, Chari M, Li X, Light PE, et al. Upper

intestinal lipids trigger a gut-brain-liver axis to regulate glucose pro-

duction. Nature 2008;452:1012–6.

[31] Matzinger D, Degen L, Drewe J, Meuli J, Duebendorfer R,

Ruckstuhl N, et al. The role of long chain fatty acids in regulating

food intake and cholecystokinin release in humans. Gut 2000;

46:688–93.

[32] Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP,

Bortoluzzi MN, et al. The stomach is a source of leptin. Nature

1998;394:790–3.

[33] Barrachina MD, Martinez V, Wang L, Wei JT, Tache Y. Synergistic

interaction between leptin and cholecystokinin to reduce short-term

food intake in mice. Proc Natl Acad Sci U S A 1997;94:10455–60.

[34] Fox EA, Murphy MC. Factors regulating vagal sensory development:

potential role in obesities of developmental origin. Physiol Rev 2008;

94:90–104.

[35] Komori T, Morikawa Y, Nanjo K, Senba E. Induction of brain-derived

neurotrophic factor by leptin in the ventromedial hypothalamus.

Neuroscience 2006;139:1107–15.

U. N. Das / Nutrition 26 (2010) 459–473470

[36] Hirano H, Day J, Fibiger HC. Serotonergic regulation of acetylcholine

release in rat frontal cortex. J Neurochem 1995;65:1139–45.

[37] Zhou FM, Liang Y, Dani JA. Endogenous nicotinic cholinergic activ-

ity regulates dopamine release in the striatum. Nat Neurosci 2001;

4:1224–9.

[38] Bartness TJ, Kay Song C, Shi H, Bowers RR, Foster MT. Brain-adi-

pose tissue cross talk. Proc Nutr Soc 2005;64:53–64.

[39] Huang LZ, Winzer-Serhan UH. Nicotine regulates mRNA expression

of feeding peptides in the arcuate nucleus in neonatal rat pups. Dev

Neurobiol 2007;67:363–77.

[40] Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central

administration of oleic acid inhibits glucose production and food in-

take. Diabetes 2002;51:271–5.

[41] Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypo-

thalamic carnitine palmitoyltransferase-1 decreases food intake and

glucose production. Nat Med 2003;9:756–61.

[42] Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aquilar-

Bryan L, et al. Hypothalamic sensing of circulating fatty acids is re-

quired for glucose homeostasis. Nat Med 2005;11:320–7.

[43] Suresh Y, Das UN. Protective action of arachidonic acid against al-

loxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leu-

kot Essent Fatty Acids 2001;64:37–52.

[44] Suresh Y, Das UN. Long-chain polyunsaturated fatty acids and chem-

ically-induced diabetes mellitus: effect of u-6 fatty acids. Nutrition

2003;19:93–114.

[45] Suresh Y, Das UN. Long-chain polyunsaturated fatty acids and chemi-

cally-induced diabetes mellitus: effect of u-3 fatty acids. Nutrition

2003;19:213–28.

[46] Suresh Y, Das UN. Differential effect of saturated, monounsaturated,

and polyunsaturated fatty acids on alloxan-induced diabetes mellitus.

Prostaglandins Leukot Essent Fatty Acids 2006;74:199–213.

[47] Richard D, Guesdon B, Timofeeva E. The brain endocannabinoid sys-

tem in the regulation of energy balance. Best Pract Res Clin Endocri-

nol Metab 2009;23:17–32.

[48] Di Marzo V. The endocannabinoid system in obesity and type 2 dia-

betes. Diabetologia 2008;51:1356–67.

[49] Romanova IV, Ramos EJ, Xu Y, Quinn R, Chen C, George ZM, et al.

Neurobiologic changes in the hypothalamus associated with weight

loss after gastric bypass. J Am Coll Surg 2004;199:887–95.

[50] Xu Y, Ramos EJ, Middleton F, Romanova I, Quinn R, Chen C, et al.

Gene expression profiles post Roux-en-Y gastric bypass. Surgery

2004;136:246–52.

[51] Tonra JR, Ono M, Liu X, Garcia K, Jackson C, Yancoupoulos GD,

et al. Brain-derived neurotrophic factor improves blood glucose con-

trol and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/

lepr(db) mice. Diabetes 1999;48:588–94.

[52] Ono M, Itakura Y, Nonomura T, Nakagawa T, Nakayama C, Taiji M,

Noguchi H. Intermittent administration of brain-derived neurotrophic

factor ameliorates glucose metabolism in obese diabetic mice. Metabo-

lism 2000;49:129–33.

[53] Cao L, Lin E-JD, Cahill MC, Wang C, Liu X, During MJ. Molecular

therapy of obesity and diabetes by a physiological autoregulatory ap-

proach. Nat Med 2009;15:447–54.

[54] Nonomura T, Tsuchida A, Ono-Kishino M, Nakagawa T, Taiji M,

Noguchi H. Brain-derived neurotrophic factor regulates energy ex-

penditure through the central nervous system in obese diabetic

mice. Int J Exp Diabetes Res 2001;2:201–9.

[55] Suwa M, Kishimoto H, Nofuji Y, Nakano H, Sasaki H, Radak Z,

Kumagai S. Serum brain-derived neurotrophic factor level is in-

creased and associated with obesity in newly diagnosed female

patients with type 2 diabetes mellitus. Metabolism 2006;55:

852–7.

[56] Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P,

Rasmussen P, Erikstrup C, et al. Brain-derived neurotrophic factor

(BDNF) and type 2 diabetes. Diabetologia 2007;50:431–8.

[57] Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR,

et al. Brain-derived neurotrophic factor regulates energy balance

downstream of melanocortin-4 receptor. Nat Neurosci 2003;

6:736–42.

[58] Das UN. Is type 2 diabetes mellitus a disorder of the brain? Nutrition

2002;18:667–72.

[59] Tran PV, Akana SF, Malkovska I, Dallman MF, Parada LF,

Ingraham HA. Diminished hypothalamic bdnf expression and impaired

VMH function are associated with reduced SF-1 gene dosage. J Comp

Neurol 2006;498:637–48.

[60] Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central mel-

anocortin receptors regulate insulin action. J Clin Invest 2001;

108:1079–85.

[61] Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S.

Ghrelin stimulates GH but not food intake in arcuate nucleus ablated

rats. Endocrinology 2002;143:3268–75.

[62] Kamegai Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I.

Chronic central infusion of ghrelin increases hypothalamic neuropep-

tide Y and Agouti-related protein mRNA levels and body weight in

rats. Diabetes 2001;50:2438–43.

[63] Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E,

Boyadjian R. Insulin regulates plasma ghrelin concentration. J Clin

Endocrinol Metab 2002;87:3997–4000.

[64] Broglio F, Gottero C, Van Koetsveld P, Prodam F, Destefanis S,

Benso A, et al. Acetylcholine regulates ghrelin secretion in humans.

J Clin Endocrinol Metab 2004;89:2429–33.

[65] Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L,

et al. Family trios analysis of common polymorphisms in the obesta-

tin/ghrelin, BDNF and AGRP genes in patients with anorexia nervosa:

association with subtype, body-mass index, severity and age of onset.

Psychoneuroendocrinology 2007;32:106–13.

[66] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM.

Positional cloning of the mouse obese gene and its human homologue.

Nature 1994;372:425–32.

[67] Huang Q, Viale A, Picard F, Nahon J, Richard D. Effects of leptin

on melanin-concentrating hormone expression in the brain of lean

and obese Lep(ob)/Lep(ob) mice. Neuroendocrinology 1999;

69:145–53.

[68] Das UN. Obesity, metabolic syndrome X, and inflammation. Nutrition

2002;18:430–2.

[69] Das UN. Aberrant expression of perilipins and 11-b-HSD-1 as molec-

ular signatures of metabolic syndrome X in South East Asians. J Assoc

Phys India 2006;54:637–49.

[70] Sinha S, Rathi M, Misra A, Kumar V, Kumar M, Jagannathan NR,

et al. Subclinical inflammation and soleus muscle intramyocellular

lipids in healthy Asian Indian males. Clin Endocrinol (Oxf) 2005;

63:350–5.

[71] Das UN. A perinatal strategy to prevent coronary heart disease. Nutri-

tion 2002;19:1022–7.

[72] Albert MA, Glynn RJ, Ridker PM. Plasma concentration of C-reactive

protein and the calculated Framingham coronary heart disease risk

score. Circulation 2003;108:161–5.

[73] van der Meer IM, de Maat MP, Hak AE, Kilian AJ, Del Sol AI, Van

Der Kuip DA, et al. C-reactive protein predicts progression of athero-

sclerosis measured as various sites in the arterial tree. The Rotterdam

study. Stroke 2002;33:2750–5.

[74] Luc G, Bard J-M, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P,

et al. C-reactive protein, interleukins-6, and fibrinogen as predictors

of coronary heart disease. The PRIME study. Arterioscler Thromb

Vasc Biol 2003;23:1255–61.

[75] Engstrom G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgarde F.

Inflammation-sensitive plasma proteins are associated with future

weight gain. Diabetes 2003;52:2097–101.

[76] Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH,

Resnick HE, Tracy RP. The relation of markers of inflammation to

U. N. Das / Nutrition 26 (2010) 459–473 471

the development of glucose disorders in the elderly. Diabetes 2001;

50:2384–9.

[77] Kim MJ, Yoo KH, Park HS, Chung SM, Jin CJ, Lee Y, et al. Plasma

adiponectin and insulin resistance in Korean type 2 diabetes mellitus.

Yonsei Med J 2005;46:42–50.

[78] Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the met-

abolic syndrome, and risk of incident cardiovascular events. Circula-

tion 2003;107:391–7.

[79] Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM.

Relation between a diet with a high glycemic load and plasma concen-

trations of high-sensitivity C-reactive protein in middle-aged women.

Am J Clin Nutr 2002;75:492–8.

[80] Pepys MB, Hirshfiled GM. C-reactive protein: a critical update. J Clin

Invest 2003;111:1805–12.

[81] Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M,

Krausz T, Pepys MB. C-reactive protein and complement are impor-

tant mediators of tissue damage in acute myocardial infarction. J Exp

Med 1999;190:1733–9.

[82] Gill R, Kemp JA, Sabin C, Pepys MB. Human C-reactive protein in-

creases cerebral infarct size after middle cerebral artery occlusion in

adult rats. J Cereb Blood Flow Metab 2004;24:1214–8.

[83] Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC,

Bellotti V, et al. Targeting C-reactive protein for the treatment of car-

diovascular disease. Nature 2006;440:1217–21.

[84] Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F,

Ciotola M, et al. Inflammatory cytokine concentrations are acutely in-

creased by hyperglycemia in humans. Role of oxidative stress. Circu-

lation 2002;106:2067–72.

[85] Kirwan JP, Krishnan RK, Weaver JA, Del Aguila LF, Evans WJ. Hu-

man aging is associated with altered TNF-a production during hyper-

glycemia and hyperinsulinemia. Am J Physiol Endocrinol Metab

2001;281:E1137–43.

[86] Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE. Hy-

perglycemia-induced production of acute phase reactants in adipose

tissue. J Biol Chem 2001;276:42077–83.

[87] Cho HJ, Kim JK, Zhou XF, Rush RA. Increased brain-derived neu-

rotrophic factor immunoreactivity in rat dorsal root ganglia and spi-

nal cord following peripheral inflammation. Brain Res 1997;

764:269–72.

[88] Oddiah D, Anand P, McMahon SB, Rattray M. Rapid increase of

NGF, BDNF and NT-3 mRNAs in inflamed bladder. Neuroreport

1998;9:1455–8.

[89] Virchow JC, Julius P, Lommatzsch M, Luttmann W, Renz H, Braun A.

Neurotrophins are increased in bronchoalveolar lavage fluid after seg-

mental allergen provocation. Am J Respir Crit Care Med 1998;

158:2002–5.

[90] Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T,

Klinkert WE, et al. Activated human T cells, B cells, and monocytes

produce brain-derived neurotrophic factor in vitro and in inflamma-

tory brain lesions: a neuroprotective role of inflammation? J Exp

Med 1999;189:865–70.

[91] Tabakman R, Lecht S, Sephanova S, Arien-Zakay H, Lazarovici P. In-

teractions between the cells of the immune and nervous system: neuro-

trophins as neuroprotection mediators in CNS injury. Prog Brain Res

2004;146:387–401.

[92] Makar TK, Trisler D, Sura KT, Sultana S, Patel N, Bever CT. Brain

derived neurotrophic factor treatment reduces inflammation and apo-

ptosis in experimental allergic encephalomyelitis. J Neurol Sci 2008;

270:70–6.

[93] Ricci A, Mariotta S, Saltini C, Falasca C, Giovagnoli MR, Mannino F,

et al. Neurotrophin system activation in bronchoalveolar lavage fluid

immune cells in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse

Lung Dis 2005;22:186–94.

[94] Hahn C, Islamian AP, Renz H, Nockher WA. Airway epithelial cells

produce neurotrophins and promote the survival of eosinophils during

allergic airway inflammation. J Allergy Clin Immunol 2006;

117:787–94.

[95] Bennedich Kahn L, Gustafsson LE, Olgart Hoglund C. Brain-derived

neurotrophic factor enhances histamine-induced airway responses and

changes levels of exhaled nitric oxide in guinea pigs in vivo. Eur J

Pharmacol 2008;595:78–83.

[96] Lommatzsch M, Braun A, Mannsfeldt A, Botchkarev VA,

Botchkarev NV, Paus R, et al. Abundant production of brain-derived

neurotrophic factor by adult visceral epithelia. Am J Pathol 1999;

155:1183–93.

[97] Rost B, Hanf G, Ohnemus U, Otto-Knapp R, Groneberg DA,

Kunkel G, Noga O. Monocytes of allergics and non-allergics produce,

store and release the neurotrophins NGF, BDNF and NT-3. Regul Pept

2005;124:19–25.

[98] Noga O, Englmann C, Hanf G, Grutzkau A, Kunkel G. The production,

storage and release of the neurotrophins nerve growth factor, brain-de-

rived neurotrophic factor and neurotrophin-3 by human peripheral eo-

sinophils in allergics and non-allergics. Clin Exp Allergy 2003;

33:649–54.

[99] Rihl M, Kruithof E, Barthel C, De Keyser F, Veys EM, Zeidler H,

et al. Involvement of neurotrophins and their receptors in spondyloar-

thritis synovitis: relation to inflammation and response to treatment.

Ann Rheum Dis 2005;64:1542–9.

[100] del Porto F, Aloe L, Lagana B, Triaca V, Nofroni I, D’Amelio R.

Nerve growth factor and brain-derived neurotrophic factor levels in

patients with rheumatoid arthritis treated with TNF-alpha blockers.

Ann N Y Acad Sci 2006;1069:438–43.

[101] Grimsholm O, Guo Y, Ny T, Forsgren S. Expression patterns of neu-

rotrophins and neurotrophin receptors in articular chondrocytes and

inflammatory infiltrates in knee joint arthritis. Cells Tissues Organs

2008;188:299–309.

[102] Cai D, Holm JM, Duignan IJ, Zheng J, Xaymardan M, Chin A, et al.

BDNF-mediated enhancement of inflammation and injury in the aging

heart. Physiol Genomics 2006;24:191–7.

[103] Johansson M, Norrgard O, Forsgren S. Study of expression patterns

and levels of neurotrophins and neurotrophin receptors in ulcerative

colitis. Inflamm Bowel Dis 2007;13:398–409.

[104] di Mola FF, Friess H, Zhu ZW, Koliopanos A, Bley T, Di

Sebastiano P, et al. Nerve growth factor and Trk high affinity receptor

(TrkA) gene expression in inflammatory bowel disease. Gut 2000;

46:670–9.

[105] Raap U, Werfel T, Goltz C, Deneka N, Langer K, Bruder M, et al. Cir-

culating levels of brain-derived neurotrophic factor correlate with dis-

ease severity in the intrinsic type of atopic dermatitis. Allergy 2006;

61:1416–8.

[106] Bajzer M, Seeley RJ. Obesity and gut flora. Nature 2006;

444:1009–10.

[107] Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-

bacterial mutualism in the human intestine. Science 2005;

307:1915–20.

[108] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology:

human gut microbes associated with obesity. Nature 2006;

444:1022–3.

[109] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER,

Gordon JI. An obesity-associated gut microbiome with increased ca-

pacity for energy harvest. Nature 2006;444:1027–31.

[110] Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD,

Gordon JL. Obesity alters gut microbial ecology. Proc Natl Acad

Sci U S A 2005;102:11070–5.

[111] Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The

gut microbiota as an environmental factor that regulates fat storage.

Proc Natl Acad Sci U S A 2004;101:15718–23.

[112] Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mecha-

nisms underlying the resistance to diet-induced obesity in germ-free

mice. Proc Natl Acad Sci U S A 2007;104:979–84.

U. N. Das / Nutrition 26 (2010) 459–473472

[113] Varel VH, Pond WG, Pekas JC, Yen JT. Influence of high-fibre diet on

bacterial populations in gastrointestinal tracts of obese- and lean-

genotype pigs. Appl Environ Microbiol 1982;44:107–12.

[114] Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK,

et al. Effects of the gut microbiota on host adiposity are modulated by

the short-chain fatty acid binding G protein-coupled receptor, Gpr41.

Proc Natl Acad Sci U S A 2008;105:16767–72.

[115] Amar J, Burcelin R, Ruiavets JB, Cani PD, Fauvel J, Alessi MC, et al.

Energy intake is associated with endotoxemia in apparently healthy

men. Am J Clin Nutr 2008;87:1219–23.

[116] Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, et al.

Human gut microbiota in obesity and after gastric bypass. Proc Natl

Acad Sci U S A 2009;106:2365–70.

[117] Whitson BA, D’Cunha J, Hoang CD, Wu B, Ikramuddin S, Buchwald H,

et al. Minimally invasive versus open Roux-en-Y gastric bypass: effect

on immune effector cells. Surg Obes Relat Dis 2009;5:181–93.

[118] Das UN. Is metabolic syndrome X a disorder of the brain? Curr Nutr

Food Sci 2008;4:73–108.

[119] Middleton FA, Ramos EJB, Xu Y, Diab H, Zhao X, Das UN,

Meguid MM. Application of genomic technologies: DNA microarrays

and metabolic profiling of obesity in the hypothalamus and in subcuta-

neous fat. Nutrition 2004;20:14–25.

[120] Meguid M, Ramos EJB, Suzuki S, Xu Y, George ZM, Das UN, et al.

A surgical rat model of human Roux-en-Y gastric bypass. J Gastroint-

est Surg 2004;8:621–30.

[121] Das UN. Metabolic syndrome X is a low-grade systemic inflammatory

condition with its origins in the perinatal period. Curr Nutr Food Sci

2007;3:277–95.

[122] Das UN. Pathophysiology of metabolic syndrome X and its links to

the perinatal period. Nutrition 2005;21:762–73.

[123] Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC,

et al. Role of brain insulin receptor in control of body weight and re-

production. Science 2000;289:2122–5.

[124] Wu A, Ying Z, Gomez-Pinilla F. Dietary omega-3 fatty acids normalize

BDNF levels, reduce oxidative damage, and counteract learning disabil-

ity after traumatic brain injury in rats. J Neurotrauma 2004;21:1457–67.

[125] Rao JS, Ertley RN, Lee HJ, DeMar JC Jr, Arnold JT, Rapoport SI,

Bazinet RP. N-3 polyunsaturated fatty acid deprivation in rats de-

creases frontal cortex BDNF via a p38 MAPK-dependent mechanism.

Mol Psychiatry 2007;12:36–46.

[126] Innis SM, de La Presa Owens S. Dietary fatty acid composition in

pregnancy alters neurite membrane fatty acids and dopamine in new-

born rat brain. J Nutr 2001;131:118–22.

[127] de La Presa Owens S, Innis SM. Diverse, region-specific effects of ad-

dition of arachidonic and docosahexaenoic acids to formula with low

or adequate linoleic and alpha-linolenic acids on piglet brain monoam-

inergic neurotransmitters. Pediatr Res 2000;48:125–30.

[128] Peters JH, Simasko SM, Ritter RG. Modulation of vagal afferent ex-

citation and reduction of food intake by leptin and cholecystokinin.

Physiol Behav 2006;89:477–85.

[129] Ueno N, Dube MG, Inui A, Kalra PS, Kalra SP. Leptin modulates

orexigenic effects of ghrelin and attenuates adiponectin and insulin

levels and selectively the dark-phase feeding as revealed by central

leptin gene therapy. Endocrinology 2004;145:4176–84.

[130] Goto M, Arima H, Watanabe M, Hayashi M, Banno R, Sato I, et al.

Ghrelin increases neuropeptide Y and agouti-related peptide gene ex-

pression in the arcuate Nucleus in rat hypothalamic organotypic cul-

tures. Endocrinology 2006;147:5102–9.

[131] Bassil AK, Dass NB, Sanger GJ. The prokinetic-like activity of ghrelin in

rat isolated stomach is mediated via cholinergic and tachykininergic mo-

tor neurones. Eur J Pharmacol 2006;544:146–52.

[132] Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI,

Watkins LR, et al. Vagus nerve stimulation attenuates the systemic

inflammatory response to endotoxin. Nature 2000;405:458–62.

[133] Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H,

et al. Pharmacological stimulation of the cholinergic antiinflammatory

pathway. J Exp Med 2002;195:781–8.

[134] Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al.

Nicotinic acetylcholine receptor a7 subunit is an essential regulator of

inflammation. Nature 2003;421:384–7.

[135] Hersi AI, Kitaichi K, Srivastava LK, Gaudreau P, Quirion R. Dopa-

mine D-5 receptor modulates hippocampal acetylcholine release.

Brain Res Mol Brain Res 2000;76:336–40.

[136] Das UN. Alcohol consumption and risk of dementia. Lancet 2002;

360:490.

[137] Minami M, Kimura S, Endo T, Hamaue N, Horafuji M, Togashi H,

et al. Dietary docosahexaenoic acid increases cerebral acetylcholine

levels and improves passive avoidance performance in stroke-prone

spontaneously hypertensive rats. Pharmacol Biochem Behav 1997;

58:1123–9.

[138] Borkman M, Stolien LH, Pan DA, Jenkins AB, Chisholm DJ,

Campbell LV. The relation between insulin sensitivity and the fatty

acid composition of skeletal muscle phospholipids. N Engl J Med

1993;328:238–44.

[139] Das UN. A defect in the activity of D6 and D5 desaturases may be a fac-

tor predisposing to the development of insulin resistance syndrome.

Prostaglandins Leukot Essent Fatty Acids 2005;72:343–50.

[140] Ginsberg BH, Jabour J, Spector AA. Effect of alterations in membrane

lipid unsaturation on the properties of the insulin receptor of Ehrlich

ascites cells. Biochim Biophys Acta 1982;690:157–64.

[141] Somova L, Moodley K, Channa ML, Nadar A. Dose-dependent ef-

fect of dietary fish-oil (n-3) polyunsaturated fatty acids on in vivo

insulin sensitivity in rat. Methods Find Exp Clin Pharmacol 1999;

21:275–8.

[142] Huang Y-J, Fang VS, Chou Y-C, Kwok C-F, Ho L- T. Amelioration

of insulin resistance and hypertension in a fructose-fed rat model with

fish oil supplementation. Metabolism 1997;46:1252–8.

[143] Mori Y, Murakawa Y, Katoh S, Hata S, Yokoyama J, Tajima N, et al.

Influence of highly purified eicosapentaenoic acid ethyl ester on insu-

lin resistance in the Otsuka Long-Evans Tokushima fatty rat, a model

of spontaneous non-insulin dependent diabetes mellitus. Metabolism

1997;46:1458–64.

[144] Anthony K, Reed LJ, Dunn JT, Bingham E, Hopkins D, Marsden PK,

Amiel SA. Attenuation of insulin-evoked responses in brain networks

controlling appetite and reward in insulin resistance. The cerebral ba-

sis for impaired control of food intake in metabolic syndrome? Diabe-

tes 2006;55:2986–92.

[145] Flores MBS, Fernandes MFA, Ropello ER, Faria MC, Ueno M,

Velloso LA, et al. Exercise improves insulin and leptin sensitivity in

hypothalamus of Wistar rats. Diabetes 2006;55:2554–61.

[146] Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford MLJ.

Leptin inhibits hypothalamic neurons by activation of ATP-sensitive

potassium channels. Nature 1997;390:521–5.

[147] Harvey J, McKay NG, Walker KS, Van der Kay J, Downes CP,

Ashford MLJ. Essential role of phosphoinositide 3-kinase in leptin-in-

duced kATP channel activation in the rat CRI-GI insulinoma cell line.

J Biol Chem 2000;275:4660–9.

[148] Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford MLJ. In-

sulin activates ATP-sensitive Kþ channels in hypothalamic neuronsof

lean, but not obese rats. Nat Neurosci 2000;3:757–62.

[149] Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV,

Lane MD, Kuhajda FP. Reduced food intake and body weight in mice

treated with fatty acid synthase inhibitors. Science 2000;288:

2379–81.

[150] McGarry GD, Mannaert GP, Foster DW. A possible role for malonyl-

CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J

Clin Invest 1977;60:265–70.

[151] Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA fuel

sensing and insulin resistance. Am J Physiol Endocrinol Metab

1999;276:E1–18.

[152] Ramos EJB, Suzuki S, Meguid MM, Laviano A, Sato T, Chen C,

Das UN. Changes in hypothalamic neuropeptide Y and monoaminer-

gic system in tumor-bearing rats: pre- and post-tumor resection and at

death. Surgery 2004;136:270–6.

U. N. Das / Nutrition 26 (2010) 459–473 473

[153] Stranahan AM, Lee K, Martin B, Maudsley S, Golden E, Cutler RG,

Mattson MP. Voluntary exercise and caloric restriction enhance hip-

pocampal dendritic spine density and BDNF levels in diabetic mice.

Hippocampus 2009;19:951–61.

[154] Ryan AS, Nicklas BJ. Reductions in plasma cytokine levels with

weight loss improve insulin sensitivity in overweight and obese post-

menopausal women. Diabetes Care 2004;27:1699–705.

[155] Teixeira de Lemos E, Reis F, Baptista S, Pinto R, Sepodes B, Vala H,

et al. Exercise training decreases proinflammatory profile in Zucker

diabetic (type 2) fatty rats. Nutrition 2009;25:330–9.

[156] Das UN. Anti-inflammatory nature of exercise. Nutrition 2004;20:323–6.

[157] Shi X, Stevens GH, Foresman BH, Stern SA, Raven PB. Autonomic

nervous system control of the heart: endurance exercise training. Med

Sci Sports Exerc 1995;27:1406–13.